Project 4 ? SUMMARY/ABSTRACT Endometrial cancer (EC) is the most frequent gynecologic malignancy and the fourth most common cancer among women in the United States. Although cure is possible for early disease, outcomes for patients with metastatic or recurrent disease have not improved significantly over the last two decades. Based on extensive characterization by our team and The Cancer Genome Atlas, EC has a high frequency of aberrations in targetable pathways including the phosphatidylinositol 3 kinase (PI3K, 92%), ARID1A (33%), and homologous recombination (HR 22% core and 77% extended members) pathways. However, to date, targeted monotherapies have not had a major impact in EC. Thus, how to leverage the therapeutic opportunities in EC represents a major gap in knowledge that represents the overarching goal of this application. Our overall goal is: to design and implement rational combination therapy clinical trials based on high quality clinical and preclinical data and models to improve outcomes for EC patients. Aim 1 To identify and refine biomarkers of benefit in a combination trial of PARP and PI3K pathway targeted therapy in EC: Based on the underlying mutational aberrations present in EC, we are actively enrolling on the first information-rich, biopsy-embedded investigator-initiated trial targeting two nodes in the PI3K pathway (mTOR (2 dose schedules) and AKT) in combination with an effective ?trapping? PARP inhibitor, olaparib. We will test the hypothesis that combined targeting of key nodes in the PI3K pathway and PARP inhibition will demonstrate benefit in EC patients. Extensive characterization of pre- and post-treatment biopsies at the DNA, RNA and protein levels will facilitate the identification of biomarkers of benefit including our current suite of biomarkers of responsiveness to PARP and PI3K pathway inhibitors. This is a unique approach and opportunity, supported by our evidence that PI3K and HR pathways aberrations are extremely common in EC, likely rendering patients sensitive to combined PI3K and PARP pathway inhibition. Aim 2 To establish a preclinical framework to identify rational combination targeted therapies for EC to be evaluated in future EC clinical trials: Emergence of adaptive resistance to targeted therapies contributes to the lack of efficacy of monotherapy. We have used our Combinatorial Adaptive Resistance (CART) platform to identify a limited number of potential additional rational combinations for validation, aimed at adaptive resistance induced by targeting the DNA damage response. This Aim will focus on in vitro and in vivo preclinical data and biomarkers to prioritize combinations in future trials. To rapidly translate these rational drug combinations to clinical trials in this SPORE, AstraZeneca has signed a contract to provide funding for EC clinical trials with their complete therapeutic pipeline.